Anion and sugar recognition by 2,6-pyridinedicarboxamide bis-boronic acid derivatives

Article abstract of DOI:10.1515/hc-2017-0054

Two 2,6-pyridinedicarboxamide derivatives containing arylboronic acid fragments were prepared and fully characterized including X-ray crystal diffraction analysis of a pinacol ester. These compounds are potential bifunctional receptors for sugars and anions. Acid dissociation and stability constants for complexation of both receptors with glucose and fructose were determined by potentiometric titrations in aqueous DMSO. Also, binding of alizarin red S indicator was studied spectrophotometrically and a highly sensitive detection of fructose by an indicator displacement assay was proposed. Complexation with anions was studied by ₁H NMR titrations in DMSO-d₆. Binding of acetate anion occurs only via hydrogen bonding to OH groups of boronic acid fragments and does not affect signals of NH protons but chloride anion induces large shift of the signals of NH protons and small shifts of the signals of OH groups. This behavior makes possible anion discrimination based on preference in the type of binding site rather than simply on anion basicity as is typical for majority of neutral hydrogen bonding anion receptors.

Full text of DOI:10.1515/hc-2017-0054

Heterocycl. Commun. 2017; aop
Mayte A. Martínez-Aguirre, Diego Martínez Otero, Magali L. Álvarez-Hernández,
Teresa Torres-Blancas, Alejandro Dorazco-González and Anatoly K. Yatsimirsky*
Anion and sugar recognition by
2,6-pyridinedicarboxamide bis-boronic
acid derivatives
DOI 10.1515/hc-2017-0054
Received March 12, 2017; accepted May 3, 2017
Introduction
Abstract: Two 2,6-pyridinedicarboxamide derivatives There is a significant current interest in development of
containing arylboronic acid fragments were prepared ‘multi-channel’ or ‘multifunctional’ sensors containing an
and fully characterized including X-ray crystal diffraction array of recognition sites for detection of several analytes
analysis of a pinacol ester. These compounds are potential [1–4]. By the moment most such sensors are designed for
bifunctional receptors for sugars and anions. Acid disso- detection of multiple metal ions [2]. Important analytes of
ciation and stability constants for complexation of both other types involve anions and carbohydrates which are
receptors with glucose and fructose were determined by frequent components of many biological, environmental
potentiometric titrations in aqueous DMSO. Also, bind- and nutritional systems [5–9]. In this paper, we report
ing of alizarin red S indicator was studied spectrophoto- synthesis and characterization of two dicarboxamidedi-
metrically and a highly sensitive detection of fructose by boronic acids as first examples of receptors of this type
an indicator displacement assay was proposed. Compl- exploiting dicarboxamide and boronic acid moieties as
1
exation with anions was studied by H NMR titrations in anion and sugar receptor sites.
DMSO-d6. Binding of acetate anion occurs only via hydro-
2,6-Pyridinedicarboxamide and structurally related
gen bonding to OH groups of boronic acid fragments and isophthalamide derivatives initially suggested as simple
does not affect signals of NH protons but chloride anion yet efficient hydrogen bonding anion receptors [10] are
induces large shift of the signals of NH protons and small currently among most popular building blocks and scaf-
shifts of the signals of OH groups. This behavior makes folds employed in design of numerous cyclic and acyclic
possible anion discrimination based on preference in the receptors for guests of distinct types including anions,
type of binding site rather than simply on anion basic- cations and neutral molecules [11–15]. Pyridinedicarbo-
ity as is typical for majority of neutral hydrogen bonding xamides are used more often because they are better pre-
anion receptors.
organized for anion binding [14, 15]. In a proposed here
design of a bifunctional receptor a 2,6-pyridinedicarbo-
xamide is used both as an anion recognition site and as a
scaffold for incorporation of boronic acid groups for sugar
recognition. However, the actual role of boronic acids may
be more complex because they also may participate in
anion recognition. Lewis acidity of boronic acids toward
anions is well documented and widely employed in design
of anion, mostly fluoride, receptors [16–19]. It has been
shown recently that the B(OH)2 group acts also as a strong
proton donor toward anions [20], which possibly may
compete with ‘classical’ hydrogen bonding anion recep-
tors like dicarboxamides. It seems therefore interesting to
see which site would be preferable for binding of anions
of distinct types within a receptor possessing both a dicar-
boxamide and a boronic acid recognition sites. Following
from above considerations we have prepared bifunctional
receptors 1 and 2 as well as a simple monofunctional recep-
tor 3 lacking boronic acid groups as a reference compound.
Keywords: anion recognition; boronic acid 2,6-pyridinedi-
carboxamide; sugar recognition.
*Corresponding author: Anatoly K. Yatsimirsky, Facultad de
Química, Universidad Nacional Autónoma de México, 04510 México,
DF, México, e-mail: anatoli@unam.mx
Mayte A. Martínez-Aguirre: Facultad de Química, Universidad
Nacional Autónoma de México, 04510 México, DF, México
Diego Martínez Otero, Magali L. Álvarez-Hernández, Teresa
Torres-Blancas and Alejandro Dorazco-González: Centro Conjunto
de Investigación en Química Sustentable UAEM-UNAM, Instituto
de Química, Universidad Nacional Autónoma de México, Carretera
Toluca-Atlacomulco Km 14.5, C. P. 50200, Toluca, Estado de México,
México
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ꢀM.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acids
2ꢀ
Numbered free-standing structures (without legends):
O
O
O
O
N
N
O
O
N
N
N
N
N
H
H
H
H
N
N
H
H
HO
OH
B
B
B
B
OH
OH
HO
OH
HO
OH
1
2
3
All compounds are practically insoluble in water.
The acid-base and sugar binding properties of 1 and 2
Results and discussion
Receptors 1–3 were prepared by reacting 2,6-pyridin- were determined by potentiometric titrations in 50%
edicarbonyl dichloride with respective isomers of ami- vol. aqueous DMSO. Figure 2 shows the titration plots
nophenylboronic acid or with aniline. Figure 1 shows the for 1 alone and in the presence of excess of glucose or
structure of pinacol ester of 2 determined by X-ray diffrac- fructose. Similar plots were obtained for 2. The plot for
tion analysis of a crystal grown from methanol. Crystal- 1 alone has the shape of a single ‘wave’ with an upward
lographic data for pinacol ester of 2 are given in Table S1 break in pH at the point when two mole equivalents of
(Supporting Information). The receptor is nearly planar NaOH are added. Such profile is indicative of deproto-
with convergent NH bonds directed inside the cavity. The nation of two boronic acid groups with relatively close
cavity size with distances between protons of NH groups, pKa values. Additions of sugars induce strong downward
3.063 Å, and between protons of ortho-CH groups, 4.101 Å, shifts of titration curves to lower pH values and a more
is optimal for inclusion of chloride anion via hydrogen pronounced break at two mole equivalents of added
bonding chelation with NH and CH donors [21]. Boronic NaOH, confirming formation of anionic tetrahedral
acid groups are separated by a large distance of 12.7 Å, hydroxo-complexes of boronic acid esters [22–24] with
obviously too large to allow chelation of a guest.
both boronic acid groups.
O1
O4
N1
N2
N3
H3a
H2a
O7
O5
O3
B1
B2
O6
O2
Figure 1ꢁMolecular structure of pinacol ester of 2 crystallized with a methanol molecule.
Ellipsoids are drawn at the 50% probability level.
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M.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acidsꢀ
ꢀ3
The first pKa values of receptors 1 and 2 are signifi-
cantly higher than that of phenylboronic acid in water,
most probably due to the solvent effect. A smaller pKa of 1
reflects a larger electron acceptor effect of the N-acyl group
in meta position (more positive σm than σp) [25] of boronic
acid. The second pKa values are larger than the first values
due to both statistical and electronic effects. Increased pKa
values of boronic acids 1 and 2 have the expected negative
effect on ester formation with polyols, which is reflected in
much smaller β11-1 values for 1 and 2 as compared to those
for stronger phenylboronic acid. However, the stability of
boronate esters expressed in terms of Ktet1 (Scheme 1) is
higher for 1 and 2. The relationship between these con-
stants is given by equation (3) [24] and the respective cal-
culated values of logKtet1 are shown in Table 1. Evidently,
14
13
12
11
10
9
1 alone
1 + Glucose
1 + Fructose
8
7
6
0.0
0.4
0.8
1.2
1.6
a
2.0
2.4
2.8
3.2
K
tet1 for glucose is 5 and 3 times larger with 1 and 2, respec-
tively, compared to phenylboronic acid. For fructose, the
effect is even larger: 40 and 10 times, respectively.
Figure 2ꢁPotentiometric titrations of 2.1 mM receptor 1 alone (solid
squares) and in the presence of 0.2 M glucose (open squares)
or fructose (solid triangles) in 50% vol. aqueous DMSO; a is the
number of added equivalents of NaOH.
logKtet1 = logβ11−1 + pKa1
(3)
The results of potentiometric titrations did not allow
to determine β11-2 which would correspond to formation
The titration results were analyzed in terms of general of the monoester with deprotonated second boronic acid
equation (1) where M is the neutral receptor molecule, L group (6 in Scheme 1). This means low degree of forma-
is the neutral form of the sugar, H is proton and stability tion of this species. Without this equilibrium constant we
constants βpqr are defined as in equation (2). By testing dif- cannot, however, calculate the Ktet2 value corresponding to
ferent combinations of p, q, r values for the fitting of the
formation of the final dianionic diester 7 (Scheme 1), but
the overall stability of this species should be very large as
follows from the species distribution diagrams shown for
1 in Figure 3. This Figure illustrates the species distribu-
tion diagrams for interaction of 1 with glucose and fruc-
tose. It shows the degree of formation of distinct species
(1)
(2)
pM + qL + rH ꢀ MpLqHr
[MpLqHr]
βpqr
=
.
[M]p[L]q[H]r
titration results with Hyperquad program we found the as percentage of total concentration of the receptor at
best fit with a set of the equilibrium constants given in variable pH calculated for 0.1 mM receptor and excess of a
Table 1 which correspond to a set of deprotonation and sugar (10 mM for glucose and 1 mM for more tightly bound
association equilibria illustrated in Scheme 1. For com- fructose) using the equilibrium constants from Table 1. For
parison, corresponding literature data for phenylboronic comparison, the dashed lines show calculated profiles for
acid in water are also included in Table 1.
phenylboronic acid in water.
Table 1ꢁAcid dissociation and stability constants of sugar complexes for receptors 1 and 2 (50% DMSO, 0.1 M NaCl).
a
1
2
PhB(OH)2
pKa1
pKa2
10.34ꢂ ꢂ0.03
11.22ꢂ ꢂ0.04
11.40ꢂ ꢂ0.06
12.3ꢂ ꢂ0.1
8.9
Glucose
Fructose
Glucose
Fructose
Glucose
Fructose
logβ11-1
logβ12-2
logKtet1
−7.48ꢂ ꢂ0.04
−15.28ꢂ ꢂ0.02
2.86
−5.18ꢂ ꢂ0.02
−11.55ꢂ ꢂ0.03
5.16
−8.81ꢂ ꢂ0.05
−19.13ꢂ ꢂ0.06
2.59
−6.9ꢂ ꢂ0.2
NDb
−6.75
−5.36
4.5
2.15
3.54
aPhenylboronic acid in water, data are from [22, 23].
bFitting of titration results did not require a β12-2 value.
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4ꢀ
ꢀM.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acids
HO
OH
HO
HO
OH
HO
OH
OH
K
p
K
p
a2
a1
-
-
-
B
B
R
B
B
R
B
B
R
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
K'tet1
+
+
Ktet1
HO
OH
HO
OH
K'
p
a2
-
-
B
-
B
R
B
B
R
O
HO
HO
O
O
HO
O
6
5
HO
HO
+
Ktet2
HO
OH
-
-
B
B
R
O
O
O
O
7
Scheme 1ꢁ
Let us consider first the results for glucose (Figure 3A). Figure 3A the degree of ester formation of phenylboronic
The distribution curve for monoester 5 reaches the acid with glucose at pH 7.4 is only about 4% while at pH
maximum of 40% at pH 9.7 and then goes down with 9.5 in 50% DMSO the total degree of ester formation (5ꢀ+ꢀ7,
concomitant increase in the fraction of the diester 7. The see Scheme 1) is about 70%.
fraction of mono-deprotonated 1 reaches the maximum of
In case of fructose with a much higher Ktet1 value an
6% at the same pH and the doubly deprotonated form as increased degree of ester formation is observed for 1 as
well as the ester 6 do not contribute noticeably at any pH. compared to phenylboronic acid already at pH around
Instead, a rapid growth of the fraction of diester 7 which 7 in both media (Figure 3B). At higher pH values the
exceeds 90% above pH 11 is observed. Such behavior may complexation of 1 becomes nearly quantitative with
be observed if both Ktet2 and K′tet1 are larger than Ktet1. Cur- low fraction of free boronic acid anion. These results
rently, we cannot provide a satisfactory explanation for show that receptor 1 could serve as a sensitive sensor
this phenomenon, but it is in line with our previous obser- for fructose, but it lacks suitable spectral properties.
vation of co-operative formation of diester of 1,4-benzen- The problem can be solved by using an indicator dis-
ediboronic acid with a catechol ligand [26]. Comparison of placement assay. We chose as an indicator the most
distribution curves for 1 with those for phenylboronic acid popular catechol-type dye alizarin red S (ARS) [23, 28].
at first glance indicate worse performance of the former Figure 4 shows the results of spectrophotometric titra-
since the distribution curves for it are shifted to higher pH tion of ARS by 1 at pH 8 which demonstrates character-
values. It must be considered, however, that the presence istic blue shift of the absorption maximum. Fitting of
of DMSO as a co-solvent shifts the autoprotolysis con- the titration results to equation (4) allowed us to cal-
stant of water (pKw) and therefore shifts the whole scale culate the association constant Kꢀ=ꢀ(4.6ꢀ ꢀ0.4)ꢀ×ꢀ104 M−1.
of pH [27]. In 50% (v/v) DMSO the value of pKw equals 15.9 The fitting to equation (4), which implies a 1:1 complexa-
instead of 13.8 in water (at ionic strength 0.1 M) which tion equilibrium was possible because in this experiment
means that solutions of equal basicity have pH values by an excess of receptor to the guest was employed and
2.1 units higher in 50% DMSO than in pure water. Thus, therefore predominantly a 1:1 complex was formed. For
for a typical ‘physiological’ pH of 7.4 in water the equiva- isomeric receptor 2, Kꢀ=ꢀ(3.0ꢀ ꢀ0.3)ꢀ×ꢀ104 M−1 was obtained.
lent value in 50% DMSO is pH 9.5. As can be seen from The respective binding constant of ARS to phenylboronic
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M.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acidsꢀ
ꢀ5
A
B
OH
HO
HO
OH
OH
HO
-
OH
-
B
R B
B R B
O
O
O
O
100
80
60
40
20
0
100
80
60
40
20
0
B
R
B
PhB(OH)2
HO
HO
O
O
O
O
OH
-
HO
HO
OH
-
R B
O
B
HO
R
B
O
B
HO
OH
OH
O
B R B
O
OH
HO
OH
-
Ph
B
PhB(OH)2
-
O
O
Ph
B
O
O
–
PhB(OH)3
-
PhB(OH)3
pH 7.4
HO
B R B
HO
OH
HO
B R B
HO
OH
pH 7.4
-
-
OH
OH
OH
OH
7
8
9
10
11
12
6
7
8
9
10
11
pH
pH
Figure 3ꢁSpecies distribution diagrams for 0.1 mM receptor 1 in the presence of 10 mM glucose (A) or 1 mM fructose (B) in 50% v/v DMSO/
water.
Red lines show the relative concentrations of boronate esters. Dashed lines show the distribution curves calculated for phenylboronic acid
in water with the same concentrations of sugars.
8.0 showed a linear response to fructose concentration up
to 8 mM with detection limit of 0.05 mM.
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.50
0.45
0.40
0.35
Anion recognition properties of 1–3 were studied
1
by H NMR titrations in DMSO-d6. We chose two anions
which represent two distinct types of anionic species:
highly basic planar triangular AcO− and low basic spher-
ical Cl−. Titration results for a monofunctional receptor
3 are shown in Figure 5. Both anions induce downfield
shifts of the signals of NH protons and smaller downfield
shifts of C-protons in ortho position of the phenyl ring
(doublet at 7.92 ppm) together with small upfield shifts
of the signals of meta and para protons of phenyl rings.
Downfield shifts are indicative of hydrogen bonding,
which therefore occurs as chelation of anions by NH and
ortho-C-protons and upfield shifts reflect small electron
donor inductive effect from the bound anion. Analysis of
titration profiles by using a HypNMR program gives the
association constants collected in Table 2 and the com-
plexation induced shifts of the signals of NH protons at
saturation 1.06 and 1.26 ppm for chloride and acetate
0.00
0.05
0.10
0.15
0.20
[2], mMv
400 450
500 550 600 650
Wavelength (nm)
700 750
Figure 4ꢁSpectrophotometric titration of 0.1 mM ARS with 1 in 50%
v/v DMSO/water at pH 8.0.
The inset shows the fitting of titration profile at 485 nm to equation (4).
acid in water at pH 7.4, Kꢀ=ꢀ1.5ꢀ×ꢀ103 M−1 [23], is much lower. anions, respectively. Titration results for bifunctional
Additions of fructose to the mixture of 1 and ARS
receptors 1 and 2 are shown in the respective Figures
6 and 7. Additions of acetate induce strong downfield
shift in the signal of protons of B(OH)2 group character-
istic of hydrogen bonding interaction and small upfield
shifts in signals of aromatic protons of phenyl groups
A = A0 +0.5(∆ε/[H]) ([H]+[G]+ K−1 −(([H]+[G]+K−1 )2
−4[H][G])0.5 )
(4)
were accompanied by restoration of the absorbance of free which can be attributed to an inductive effect of bound
ARS and the calibration plot constructed at 555 nm at pH anion, but practically they do not affect the signals of
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6ꢀ
ꢀM.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acids
-
-
[AcO ] = 20 mM
[CI ] = 55 mM
12
11
10
9
9
8
7
6
5
4
3
2
1
8
7
6
5
4
3
2
-
-
[AcO ] = 0
[CI ] = 0
1
8.6 8.5 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1
ppm
11.3 11.2 11.1 11.0 8.5 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1
ppm
11.5 11.4 11.3 11.2 11.1 11.0 10.9
Figure 5ꢁ1H NMR titrations of 5 mM 3 by chloride (A) and acetate (B) anions in DMSO-d6.
Spectra were recorded at increased concentrations of added anion as a tetrabutylammonium salt from bottom to top of the Figure.
Table 2ꢁComplex formation constants for anions in DMSO.
no interaction with boronic acid group of 1 is observed.
In the case of receptor 2 (Figure 7B) binding of chloride
to dicarboxamide fragment occurs via hydrogen bonding
to NH and ortho-CH (signal at 7.9 ppm experiencing sig-
nificant downfield shift upon titration) in accordance with
what is expected on basis of structure of the receptor (see
above) and with the binding constant similar in limits of
experimental errors to that for 3. A small downfield shift
of the signal of protons of boronic acid groups indicates
hydrogen bonding of chloride but with much smaller sta-
bility constant than in the case of phenylboronic acid as
receptor (Table 2).
−1
Anionꢁ
ꢁ
K (M )
a
1ꢁ
2ꢁ
3ꢁ
PhB(OH)2
AcO
Cl−
ꢃ
ꢃ
630ꢂ ꢂ50;ꢃ
3200ꢂ ꢂ300;ꢃ
33ꢂ ꢂ3ꢃ
950
320ꢂ ꢂ30b
9.8ꢂ ꢂ0.8ꢃ
200ꢂ ꢂ20b
3.6ꢂ ꢂ0.5ꢃ
5.1ꢂ ꢂ0.9ꢃ
60
12ꢂ ꢂ1c
aData from Ref. [20].
bFormation constants for the binding of first and second anion.
cFormation constant calculated from the chemical shift of the
protons of PhB(OH)2 group.
In general, acetate shows clearly selectivity toward
boronic acid and chloride preferably binds to dicarbo-
xamide NH groups. At the same time with both mono-
functional receptors 3 and phenylboronic acid, more
basic acetate always forms more stable complexes which
induces larger shifts of the NMR signals of the respec-
tive protons. Such behavior is typical for neutral hydro-
gen bonding anion receptors which discriminate anions
mostly by their basicity. Using of bifunctional receptors
allows less trivial discrimination of anions determined by
the type of preferable interaction site.
NH protons. The fitting of titration results with HypNMR
program allowed us to determine binding constants to
both boronic acid groups given in Table 2. Formation
constants for the first acetate anion are close to that
reported for phenylboronic acid. Binding of the second
anion has a smaller constant, apparently due to the elec-
trostatic repulsion to the first bound anion. Binding of
acetate to receptor 3 involves amide groups and occurs
with much smaller binding constant (Table 2), however,
in the range of acetate concentrations employed for
titrations of 1 and 2 even with this binding constant the
observed shift of the NH signal should be about 1 ppm.
Thus, while affinity of boronic acid groups in 1 and 2 to
acetate is approximately the same as that of phenylbo-
Conclusions
ronic acid, the dicarboxamide fragment loses the affin- The first examples of bifunctional receptors designed for
ity to this anion.
recognition of sugars/polyols and anions demonstrate good
Titration of 1 by chloride (Figure 6B) induces only efficiency of detection of both types of analytes. Selectivity
small downfield shift of the signal of NH protons with the of polyol recognition follows usual trend catecholꢀꢀ>ꢀꢀfruc-
binding constant which is two times higher than that for 3. toseꢀꢀ>ꢀꢀglucose and receptors may be employed as sensors in
Although chloride forms hydrogen bonded complex with indicator displacement mode. Recognition sites for anions
phenyl boronic acid and with larger constant (Table 2) are not independent. Boronic acid responds to acetate and
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M.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acidsꢀ
ꢀ7
A
NH
B(OH)2
B(OH)2
[AcO] = 20 mM
10
9
B(OH)2
B(OH)2
8
7
B(OH)2
6
B(OH)2
5
B(OH)2
4
3
2
1
B(OH)2
B(OH)2
B(OH)2
[AcO] = 0
11.2 11.0 10.8 10.6 10.4 10.2 10.0 9.8 9.6 9.4 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 7.2
ppm
B
B(OH)2
NH
[CI–] = 50 mM
13
12
11
10
9
8
7
6
5
4
3
2
1
[CI–] = 0
8.5
8.4
8.3
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
11.1 11.0 10.9
ppm
Figure 6ꢁ1H NMR titrations of 5 mM 1 by acetate (A) and chloride (B) anions in DMSO-d6.
Spectra were recorded at increased concentrations of added anion as a tetrabutylammonium salt from bottom to top of the Figure.
the dicarboxamide fragment responds to chloride. This
creates a different type of selectivity not based on anion
basicity which usually is the principal factor in anion dis-
crimination. Further progress in development of sugar/
anion bifunctional sensors may be expected with more
water soluble optically responsive receptors, which are cur-
rently in a process of design and screening in our laboratory.
Experimental
General procedure for the synthesis of compounds 1–3
A mixture of 2,6-pyridinedicarbonyl dichloride (50 mg, 0.25 mmol)
and 3- or 4-aminophenylboronic acid (70 mg, 0.5 mmol) or aniline
(47 mg, 0.5 mmol) in dry toluene was stirred under reflux in the
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ꢀM.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acids
A
NH
[AcO–] = 20 mM
B(OH)2
9
8
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
7
6
5
4
3
2
1
B(OH)2
B(OH)2
B(OH)2
[AcO–] = 0
11.2 11.0 10.8 10.6 10.4 10.2 10.0 9.8 9.6 9.4 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8
ppm
B
B(OH)2
NH
[CI–] = 60 mM
13
12
11
10
9
8
7
6
5
4
3
2
[CI–] = 0
1
10.95
8.50 8.45 8.40 8.35 8.30 8.25 8.20 8.15 8.10 8.05 8.00 7.95 7.90 7.85 7.80
11.25
11.15
11.05
ppm
Figure 7ꢁ1H NMR titrations of 5 mM 2 by acetate (A) and chloride (B) anions in DMSO-d6.
Spectra were recorded at increased concentrations of added anion as a tetrabutylammonium salt from bottom to top of the Figure.
(t, Jꢀ=ꢀ7 Hz, 2H); 13C NMR (75 MHz, 25°C, DMSO-d6): δ 161.7, 148.9,
139.8, 138.6, 137.1, 130.4, 127.7, 127.6, 125.2, 123.7; EI-MS: m/z 405
atmosphere of nitrogen for 4 h. The resultant precipitate was col-
lected by filtration and washed with 3% NaHCO3 aqueous solution
and then with water to give 1–3 as a white powder in 92%–95% yield.
Copies of 1H and 13C NMR spectra of compounds 1–3 are given in the
online supplement.
+
[M] ; ATR-IR: νmax 3382, 2977, 1355, 1398, 1141, 1087 cm−1. Anal. Calcd
for C19H17B2N3O6: C, 56.35; H, 4.23; N, 10.38. Found: C, 56.37; H, 4.25;
N, 10.75.
[4-[[6-[(4-Boronophenyl)carbamoyl]pyridine-2-carbonyl]
amino]phenyl]boronic acid (2)ꢁ1H NMR (300 MHz, 25°C, DMSO-
d6): δ 11.05 (s, 2H), 8.43 (d, Jꢀ=ꢀ7.1 Hz, 2H), 8.30 (t, Jꢀ=ꢀ8.7 Hz, 1H 1H),
8.01 (s, 4H), 7.89 (m, 8H); 13C NMR (75 MHz, 25°C, DMSO-d6): δ 161.9,
[3-[[6-[(3-Boronophenyl)carbamoyl]pyridine-2-carbonyl]
amino]phenyl]boronic acid (1)ꢁ1H NMR (300 MHz, 25°C, DMSO-
d6): δ 11.06 (s, 2H), 8.42 (d, Jꢀ=ꢀ7 Hz, 2H), 8.30 (t, Jꢀ=ꢀ9 Hz, 1H), 8.16
(s, 2H), 8.11 (s, 4H), 7.93 (d, Jꢀ=ꢀ9 Hz, 2H), 7.63 (d, Jꢀ=ꢀ7 Hz, 2H), 7.45
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M.A. Martínez-Aguirre et al.: 2,6-Pyridinedicarboxamide bis-boronic acidsꢀ
ꢀ9
+
148.8, 140.9, 140.0, 135.2, 125.6, 124.1, 119.9; EI-MS: m/z 405 [M] ;
ATR-IR: νmax 3299, 2976, 1675, 1586, 1356, 1139 cm−1. Anal. Calcd for
C19H17B2N3O6: C, 56.35; H, 4.23; N, 10.38. Found: C, 56.38; H, 4.29;
N, 10.29.
Acknowledgments: Mayte A. Martínez-Aguirre thanks
CONACyT for the doctoral fellowship (271108). We thank
M.Sc. María de la Nieves Zavala Segovia for technical
assistance. The financial support of this research by CON-
ACyT (281251, CB239648, PDCPN247495) and FQ-UNAM-
N ,N -diphenylpyridine-2,6-dicarboxamide(3)ꢁ1HNMR(300MHz,
2
6
25°C, DMSO-d6): δ 11.04 (s, 2H), 8.43 (d, Jꢀ=ꢀ8 Hz, 2H), 8.30 (t, Jꢀ=ꢀ9 Hz, PAIP is gratefully acknowledged. T. T.-B. and M. L. A.-H.
1H), 7.94 (d, Jꢀ=ꢀ9 Hz, 4H), 7.45 (t, Jꢀ=ꢀ8 Hz, 4H), 7.20 (t, Jꢀ=ꢀ8 Hz, 2H); 13C
are grateful to DGAPA-UNAM for scholarships.
NMR (75 MHz, 25°C, DMSO-d6): δ 161.6, 148.9, 139.9, 138.0, 128.8, 125.3,
+
124.3, 121.4; EI-MS: m/z 317 [M] ; ATR-IR: νmax cm−1) 3270, 1672, 1659,
1533, 1533, 1079 cm−1. Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76; N,
References
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Supplemental Material: The online version of this article
(DOI: 10.1515/hc-2017-0054) offers supplementary material,
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